The long-term objective of these studies has been to use transgenic mice to test the hypothesis that keratinocyte growth factor (KGF; FGF-7) and other members of the fibroblast growth factor family and their cognate receptors (FGFR) regulate the growth, differentiation and function of the prostate gland and that deregulation of the FGF axis facilitates the transformation, angiogenesis and metastasis associated with prostatic cancer progression in vivo. To this end we will mechanistically address the role of the FGFR signaling axis on specific molecular events, focusing on a stringent quantitative approach to elucidate how deregulated FGFR signaling can facilitate and cooperate with the androgen signaling axis (ASX) to control growth and differentiation of the prostate gland and the development and progression of prostate cancer. We will derive significant and quantitative new insights into how peptide growth factor response pathways and steroid response pathways regulate cellular growth and differentiation signals and the molecular mechanisms FGFR and AR signaling pathways use to "cross-talk" at the molecular level. Our Specific Aims exploit dimmer-inducible FGFR1 and FGFR2 signaling system and various mutated forms of AR isolated from our spontaneous autochthonous TRAMP model to test the central hypothesis. We propose to use state-of-the-art biochemical and gene-based reporter assays, RNA based analysis including Ribonulease Protection Assays (RPAs) and Chromosome Immuno-Precipitation (CHIP) assays to identify, characterize and quantitate the molecular signaling pathways downstream of the FGFR1 and FGFR2 that act to differentially regulate cellular differentiation, and how AR signaling can cooperate or compete with these signals. Moreover, we will apply our expertise in transgenesis to establish novel lines of mice harboring specific FGFR1 variants in order to more appropriately test our hypothesis in vivo.